DESCRIPTION: This application proposes novel investigations of the natural history of injection drug use, from initiation to cessation or death, as well as studies of trends in morbidity and mortality. We propose to undertake this work in Vancouver, Canada, where the steady growth in prescription opiate (PO) misuse has become a growing concern. Accordingly, we also seek to evaluate the impact of PO misuse on the natural history of injection drug use in an environment with an active heroin market, including the impact of PO use on injecting initiation and cessation, HIV risk behavior and overdose. We also aim to characterize early injecting careers and to identify the individual, social-structural and environmental factors that shape injecting initiation, early cessation of injecting, sustained injecting, and HIV risk behavior. Focusing on established injectors, we further aim to describe the individual, social-structural and environmental factors that shape cessation of and relapse into injecting, and associated morbidity and mortality. Our project involves the creation of a unique cohort, the Vancouver Drug Users Study (V-DUS, n = 1800), which involves adults who inject drugs and non-injecting street-involved drug-using youth. Participants provide behavioral information and biological specimens for testing, repository, and use by our team and other NIDA investigators. Members of our multidisciplinary team have more than two decades of experience conducting NIDA-funded cohort-based research, most recently through studies of IDU participating in the Vancouver Injection Drug Users Study (VIDUS), which is one of the longest-standing IDU cohort studies in the world, and street-involved drug-using youth participating in the At- Risk Youth Study (ARYS). In order to take advantage of considerable efficiencies, both academic and financial, we propose merging the ARYS and VIDUS cohorts into the Vancouver Drug Users Study (V-DUS), enabling a critical additional five years of investigation into the natural history f injection drug use. Vancouver is ideally suited for the proposed study for several reasons. The city was home to one of the most explosive HIV epidemics ever documented among IDU, and Vancouver is a port of entry for illicit drugs and is now experiencing a PO misuse epidemic. Further, under the province of British Columbia's universal healthcare plan, we are able to link cohort data to various administrative databases, permitting assessments of barriers to care that are free of the confounding effects of medical insurance schemes, and our established multidisciplinary team and other NIDA investigators use our cohort platform to undertake diverse work in the areas of clinical epidemiology, social, spatial, and basic science, as well as modeling and cost-effectiveness studies. Lastly, Vancouver has been the site of the development of a range of innovative programs for IDU and therefore we plan to use this cohort infrastructure to build on our track record of evaluating highly innovative programs for IDU, as well as other naturally occurring events. Through this work, we aim to address several urgent global health challenges and inform the development of policies and interventions that seek to address illicit drug use.